Changes in cellular calcium homeostasis with aging are widely considered to produce physiologically and pathologically important changes in calcium dependent processes within the nervous system. The proposed experiments are designed to determine the molecular basis of these age-related changes in calcium homeostasis and their relation to altered neurotransmitter release, to the phosphatidylinositol (PI) cascade and to energy metabolism. In order to understand better the mechanism of altered calcium homeostasis with aging, assessment will be made of: the role of superficially bound calcium, the influx of calcium through specific calcium channels, cytosolic free calcium and the mobilization of internal calcium. Previous studies suggest that aging decreases acetylcholine release, which may impair cognition, whereas aging increases glutamate and dopamine release, which may lead to cell damage postsynaptically. To better understand the relation of the neurotransmitter changes to altered calcium homeostasis, correlations will be tested of the effects of aging on the temporal pattern of neurotransmitter release to the role of calcium influx through specific calcium channels and to the phosphatidylinositol cascade. The phosphatidylinositol cascade will be assessed with aging since its products, inositol 1,4,5-triphosphate and diacylglycerol, may regulate release of intracellular calcium modulate the phosphorylation of proteins that are related to neurotransmitter release, respectively. Whether phorbol esters, which substitute for diacylglycerol, can reverse age-related deficits will be determined. Whether magnesium or phosphatidyserine supplements, which improve age-related deficits in behavior, work through an interaction of calcium, the phosphatidylinositol cascade and neurotransmitter release will be determined. A better understanding of these age-related alterations in calcium homeostasis should help to develop better strategies for the treatment of age-related disorders in man.